The formation of post-surgical adhesions is a very common complication which occurs in up to 70-90% of cases following abdominal or pelvic surgery (Holmdahl L. et al., Eur J Surg 1997, 163(3):169-174), and in up to 40% of cases of spine surgery (Einhaus S L et al., Spine 1997, 22(13):1440-1447).
Many factors determine and/or influence the formation of post-surgical adhesions, such as mechanical trauma, post-operative bleeding, the onset of ischaemic and inflammatory phenomena and possible microbial infections.
The serous exudate that forms as a consequence of surgical trauma, if not rapidly reabsorbed, may determine notable fibroblast recruitment with consequent deposit of collagen molecules responsible for the formation of adhesion between adjacent tissues.
In conclusion, the formation of a post-surgical adhesion seems to be the direct consequence of an inflammatory process.
In the field of spine surgery, the formation of peridural fibrosis is a major post-operative risk. Indeed, following laminectomy and/or discectomy, the fibrous astrocytes (cells characteristic of the glia) produce gliotic scar tissue, the function of which is to prevent neuronal matter from leaking from the dura matrix, the outermost of the meninges covering the spinal cord, formed by fibrous connective tissue.
This is a normal phenomenon in the healing process of damaged spinal tissues, but in the post-surgical inflammatory process, this totally inelastic adhesion tissue may be produced in excess and interfere with the neuromotor processes of the nerve root and dura matrix, crush the adjacent tissues and anatomical structures, thus causing the normal movements of the spinal cord and limbs to be painful.
Any subsequent operations would be more complex, requiring longer hospitalisation and less optimistic prognoses.
For the above reasons, the prevention and/or inhibition of post-surgical adhesions, specifically peridural fibrosis, have become major objectives in medical and pharmaceutical scientific research.
Indispensable features of an effective anti-adhesion barrier are: biodegradability and biocompatibility, low or no toxicity, good adhesiveness and handling, no interference with the natural healing process of the damaged tissues, but above all the ability to prevent adhesions that may form between adjacent tissues subjected to abdominal or spine surgery.
Many different materials have been tested (both in vitro and in vivo) as possible new anti-adhesives, such as synthetic or semisynthetic membranes of polyethylene terephthalate (Dacron®), metacrylate, polylactic acid (Klopp L S et al., Neurosurg Focus 2004, 16(3):E2), polytetrafluoroethylene (Goretex®) (Llado A et al., Eur Spine 1999, 8(2): 144-150).
Other experiments have investigated the effects of irrigating with steroid and non-steroid drugs, but these materials did not meet all the necessary requirements (described above) for an anti-adhesive that can be used effectively and safely in clinical practice.
U.S. Pat. Nos. 5,017,229, 5,527,893 and 5,760,200 disclose a new type of anti-adhesive membrane (Seprafilm®) consisting of two chemically bound polymers, such as hyaluronic acid (HA) and carboxymethyl-cellulose; however, the efficacy of the new barrier is diminished by toxicity problems linked with the use of activating agents such as carbodiimide, that are necessary to the formation of chemical bonds between the two polymers.
U.S. Pat. No. 5,605,938 describes an anti-adhesive medical device (ADCON®-L) consisting of a resorbable and extrudable gel, composed of pig gelatin and dextran sulphate. The ADCON®-L gel proved very effective in the prevention of post-surgical adhesions and, for this reason, it was used by the Applicant as a control device in the animal experiments described hereafter.
Conversely, EP 1323436 discloses a new anti-adhesion barrier deriving from the combination of carboxymethyl cellulose and gellan, in a 1:(0.2-5) weight ratio. The cellulose derivative in this case represents the active agent in the adhesion prevention process, however it is known to be completely without anti-inflammatory and/or antimicrobial properties, unlike sulphated hyaluronic acid (SHA) (EP0702699 B1), the active agent in the new anti-adhesion barrier that is the subject of the present invention.
Studies have also been performed on hyaluronic acid that has not been chemically modified (U.S. Pat. No. 4,141,973), to investigate its properties as an anti-adhesion barrier, but as the polymer is easily hydrated and biodegraded, its residence time in situ is far too short to enable the complete prevention of adhesions.
For this reason, hyaluronic acid has been modified to form ester bonds inside the molecule (EP 0341745 B1) which make it effective in preventing both abdominal and pelvic adhesions (Hyalobarrier® gel based on ACP® gel) by markedly increasing the residence time of the polymer at the lesion site (EP 0850074).
The esters of hyaluronic acid (EP 0216453 B1), especially its benzyl ester (Hyaff®-11), have proved efficacious in preventing post-surgical adhesions (U.S. Pat. No. 6,723,709) as well, especially when used to make solid structures such as non-woven felts (EP 0618817 B1).
However, the validity of modified hyaluronic acid in spine surgery has never been tested.
The present invention relates to a new biomaterial deriving from the combination of sulphated hyaluronic acid and gellan, as well as to a new biomaterial exclusively formed by the gellan polymer. The biomaterials of the invention proved highly effective in preventing post-surgical adhesions, both abdominal and pelvic, and especially effective in the total prevention of the adhesions that form after spine surgery, such as laminectomy and discectomy.